title: Synthesis and biological properties of novel brefeldin A analogues.
abstract: New brefeldin A (1) analogues were obtained by introducing a variety of substituents at C15. Most of the analogues exhibited significant biological activity. (15R)-Trifluoromethyl-nor-brefeldin A (3), (15R)-vinyl-nor-brefeldin A (5), their epimers 4 and 6 as well as (15S)-ethyl-nor-brefeldin A (2) were prepared from the key building blocks 12 or 24 by Julia-Kocienski olefination with tetrazolyl sulfones and subsequent macrolactonization. The vinyl derivative 5 allowed analogues to be synthesized by hydroboration and Suzuki-Miyaura coupling. The following biological properties were assessed: (a) inhibition of cell growth of human cancer cells (NCI), (b) induction of morphological changes of the Golgi apparatus of plant and mammalian cells, and (c) influence on the replication of the enterovirus CVB3. Furthermore, conformational aspects were studied by X-ray crystal structure analysis and molecular mechanics calculations, including docking of the analogues into the brefeldin A binding site of an Arf1/Sec7-complex.
authors.affiliation: Institute of Organic Chemistry, University of Heidelberg , Im Neuenheimer Feld 270, 69120 Heidelberg, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Seehafer
authors.forename: Frank
authors.initials: F
authors.lastname: Rominger
authors.forename: Günter
authors.initials: G
authors.lastname: Helmchen
authors.forename: Markus
authors.initials: M
authors.lastname: Langhans
authors.forename: David G
authors.initials: DG
authors.lastname: Robinson
authors.forename: Başak
authors.initials: B
authors.lastname: Özata
authors.forename: Britta
authors.initials: B
authors.lastname: Brügger
authors.forename: Jeroen R P M
authors.initials: JR
authors.lastname: Strating
authors.forename: Frank J M
authors.initials: FJ
authors.lastname: van Kuppeveld
authors.forename: Christian D
authors.initials: CD
authors.lastname: Klein
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D020126:Brefeldin A / Q000031:analogs & derivatives* / Q000494:pharmacology; D029822:Enterovirus B, Human / Q000187:drug effects; D006056:Golgi Apparatus / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D020126:Brefeldin A